Laccase‐Mediated Debenzylation of N ‐Benzyl Tertiary Amines: Efficient Production of Ciprofloxacin Intermediates

Abstract This study we present an environmentally benign biphasic laccase‐TEMPO catalytic system ( n ‐butyl acetate/water) for oxidative N‐debenzylation as a safe and sustainable alternative to conventional Pd‐catalyzed hydrogenolysis. The optimized system achieves 42.3% conversion of tert‐butyl (S‐5‐benzyl‐5‐azaspiro[2.4]heptan‐7‐yl)carbamate, representing a 42‐fold enhancement over monophasic laccase catalysis (≤1%). Strategic biphasic engineering overcomes substrate solubility constraints while pH optimization (5.0) and O 2 ‐coupled TEMPO + /TEMPO redox cycling synergistically enhance catalytic efficiency. Mechanistic investigations elucidate a nonradical ionic pathway with substrate selectivity governed by electronic and steric factors. The compartmentalized system uniquely decouples enzymatic oxidation (aqueous phase) from TEMPO + regeneration (organic phase), resolving intrinsic stability limitations of homogeneous catalysis. The oxidation proceeds efficiently under mild, metal‐free co‐oxidant conditions, offering a fundamentally greener approach to pharmaceutical amine synthesis by eliminating hazardous hydrogen gas and precious metal catalysts.